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The birth and growth of the protein folding nucleus: Studies of protein folding focused on critical contacts, topology and ionic interactions
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Responsible organisation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are among the most complex molecules in the cell and they play a major role in life itself. The complexity is not restricted to just structure and function, but also embraces the protein folding reaction. Within the field of protein folding, the focus of this thesis is on the features of the folding transition state in terms of growing contacts, common nucleation motifs and the contribution of charged residues to stability and folding kinetics.

During the resent decade, the importance of a certain residue in structure formation has been deduced from Φ-value analysis. As a complement to Φ-value analysis, I present how scatter in a Hammond plot is related to site-specific information of contact formation, Φ´(βTS), and this new formalism was experimentally tested on the protein L23. The results show that the contacts with highest Φ growth at the barrier top were distributed like a second layer outside the folding nucleus. This contact layer is the critical interactions needed to be formed to overcome the entropic barrier.

Furthermore, the nature of the folding nucleus has been shown to be very similar among proteins with homologous structures and, in the split β-α-β family the proteins favour a two-strand-helix motif. Here I show that the two-strand-helix motif is also present in the ribosomal protein S6 from A. aeolicus even though the nucleation and core composition of this protein differ from other related structure-homologues.

In contrast to nucleation and contact growth, which are events driven by the hydrophobic effect, my most recent work is focused on electrostatic effects. By pH titration and protein engineering the charge content of S6 from T. thermophilus was altered and the results show that the charged groups at the protein surface might not be crucial for protein stability but, indeed, have impact on folding kinetics. Furthermore, by site-specific removal of all acidic groups the entire pH dependence of protein stability was depleted.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2008. , 73 p.
Keyword [en]
protein folding, protein stability, two-state folding, chevron plot, transition-state movements, Hammond behaviour, topology, electrostatic interactions, pH dependence, mass-action, protein engineering, pKa
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-8146ISBN: 978-91-7155-704-9 (print)OAI: oai:DiVA.org:su-8146DiVA: diva2:199692
Public defence
2008-09-26, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Opponent
Supervisors
Available from: 2008-09-04 Created: 2008-09-04Bibliographically approved
List of papers
1. Protein folding: Defining a “standard” set of experimental conditions and a preliminary kinetic data set of two-state proteins
Open this publication in new window or tab >>Protein folding: Defining a “standard” set of experimental conditions and a preliminary kinetic data set of two-state proteins
2005 In: Protein Science, ISSN 0961-8368, Vol. 14, no 3, 602-616 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25424 (URN)
Note
Part of urn:nbn:se:su:diva-8146Available from: 2008-09-04 Created: 2008-09-04Bibliographically approved
2. Scattered Hammond plots reveal second level of site-specific information in protein folding: phi' (beta++)
Open this publication in new window or tab >>Scattered Hammond plots reveal second level of site-specific information in protein folding: phi' (beta++)
2004 In: Proc Natl Acad Sci U S A, ISSN 0027-8424, Vol. 101, no 20, 7606-7611 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25425 (URN)
Note
Part of urn:nbn:se:su:diva-8146Available from: 2008-09-04 Created: 2008-09-04Bibliographically approved
3. Folding of S6 structures with divergent amino acid composition: pathway flexibility within partly overlapping foldons
Open this publication in new window or tab >>Folding of S6 structures with divergent amino acid composition: pathway flexibility within partly overlapping foldons
Show others...
2007 In: Journal of molecular biology, ISSN 0022-2836, Vol. 365, no 1, 237-248 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25426 (URN)
Note
Part of urn:nbn:se:su:diva-8146Available from: 2008-09-04 Created: 2008-09-04Bibliographically approved
4. Depletion of pH dependence upon removal of amino acids
Open this publication in new window or tab >>Depletion of pH dependence upon removal of amino acids
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25427 (URN)
Note
Part of urn:nbn:se:su:diva-8146Available from: 2008-09-04 Created: 2008-09-04 Last updated: 2010-01-13Bibliographically approved

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